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Journal articleAsai M, Li Y, Khara J, et al., 2019,
Use of the invertebrate Galleria Mellonella as an infection model to study the Mycobacterium tuberculosis complex
, Jove-Journal of Visualized Experiments, Vol: 148, ISSN: 1940-087XTuberculosis is the leading global cause of infectious disease mortality and roughly a quarter of the world’s population is believed to be infected with Mycobacterium tuberculosis. Despite decades of research, many of the mechanisms behind the success of M. tuberculosis as a pathogenic organism remain to be investigated, and the development of safer, more effective antimycobacterial drugs are urgently needed to tackle the rise and spread of drug resistant tuberculosis. However, the progression of tuberculosis research is bottlenecked by traditional mammalian infection models that are expensive, time consuming, and ethically challenging.Previously we established the larvae of the insect Galleria mellonella (greater wax moth) as a novel, reproducible, low cost, high-throughput and ethically acceptable infection model for members of the M. tuberculosis complex. Here we describe the maintenance, preparation, and infection of G. mellonella with bioluminescent Mycobacterium bovis BCG lux. Using this infection model, mycobacterial dose dependent virulence can be observed, and a rapid readout of in vivo mycobacterial burden using bioluminescence measurements is easily achievable and reproducible. Although limitations exist, such as the lack of a fully annotated genome for transcriptomic analysis, ontological analysis against genetically similar insects can be carried out. As a low cost, rapid, and ethically acceptable model for tuberculosis, G. mellonella can be used as a pre-screen to determine drug efficacy and toxicity, and to determine comparative mycobacterial virulence prior to the use of conventional mammalian models. The use of the G. mellonella-mycobacteria model will lead to a reduction in the substantial number of animals currently used in tuberculosis research.
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Journal articleTang W, Ranganathan N, Shahrezaei V, et al., 2019,
MALDI-TOF mass spectrometry on intact bacteria combined with a refined analysis framework allows accurate classification of MSSA and MRSA.
, PLoS ONE, Vol: 14, Pages: 1-16, ISSN: 1932-6203Fast and reliable detection coupled with accurate data-processing and analysis of antibiotic-resistant bacteria is essential in clinical settings. In this study, we use MALDI-TOF on intact cells combined with a refined analysis framework to demonstrate discrimination between methicillin-susceptible (MSSA) and methicillin-resistant (MRSA) Staphylococcus aureus. By combining supervised and unsupervised machine learning methods, we firstly show that the mass spectroscopy data contains strong signal for the clustering of MSSA and MRSA. Then we concentrate on applying supervised learning to extract and verify the important features. A new workflow is proposed that allows for extracting a fixed set of reference peaks so that any new data can be aligned to it and hence consistent feature matrices can be obtained. Also note that by doing so we are able to examine the robustness of the important features that have been found. We also show that appropriate size of the benchmark data, appropriate alignment of the testing data and use of an optimal set of features via feature selection results in prediction accuracy over 90%. In summary, as proof-of-principle, our integrated experimental and bioinformatics study suggests a novel intact cell MALDI-TOF to be of great promise for fast and reliable detection of MRSA strains.
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Journal articleBallinger E, Mosior J, Hartman T, et al., 2019,
Opposing reactions in coenzyme A metabolism sensitize Mycobacterium tuberculosis to enzyme inhibition (vol 363, eaau8959, 2019)
, SCIENCE, Vol: 364, ISSN: 0036-8075 -
Journal articlePeriselneris J, Nwankwo L, Schelenz S, et al., 2019,
Posaconazole for the treatment of allergic bronchopulmonary aspergillosis in patients with cystic fibrosis.
, Journal of Antimicrobial Chemotherapy, Vol: 74, Pages: 1701-1703, ISSN: 0305-7453OBJECTIVES: Allergic bronchopulmonary aspergillosis (ABPA) can accelerate lung function decline in patients with cystic fibrosis (CF). Antifungal medication can be used in addition to systemic corticosteroid treatment. PATIENTS AND METHODS: We evaluated Aspergillus-specific IgE and the use of therapeutic drug monitoring of triazoles in a retrospective analysis of 32 patients. RESULTS: There was a significant reduction in Aspergillus IgE with posaconazole but not with other triazoles (P = 0.026). Aspergillus IgE levels were inversely correlated with the therapeutic drug level of posaconazole. CONCLUSIONS: These data suggest that posaconazole is better than comparator azoles at decreasing serological response to Aspergillus and that this response was better with therapeutic levels of posaconazole.
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Journal articleEades CP, Armstrong-James DPH, 2019,
Invasive fungal infections in the immunocompromised host: Mechanistic insights in an era of changing immunotherapeutics
, Medical Mycology, Vol: 57, Pages: S307-S317, ISSN: 1369-3786The use of cytotoxic chemotherapy in the treatment of malignant and inflammatory disorders is beset by considerable adverse effects related to nonspecific cytotoxicity. Accordingly, a mechanistic approach to therapeutics has evolved in recent times with small molecular inhibitors of intracellular signaling pathways involved in disease pathogenesis being developed for clinical use, some with unparalleled efficacy and tolerability. Nevertheless, there are emerging concerns regarding an association with certain small molecular inhibitors and opportunistic infections, including invasive fungal diseases. This is perhaps unsurprising, given that the molecular targets of such agents play fundamental and multifaceted roles in orchestrating innate and adaptive immune responses. Nevertheless, some small molecular inhibitors appear to possess intrinsic antifungal activity and may therefore represent novel therapeutic options in future. This is particularly important given that antifungal resistance is a significant, emerging concern. This paper is a comprehensive review of the state-of-the-art in the molecular immunology to fungal pathogens as applied to existing and emerging small molecular inhibitors.
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Journal articleMylona E, Frankel G, 2019,
The S. Typhi effector StoD is an E3 ubiquitin ligase which binds K48- and K63-linked di-ubiquitin
, Life Science Alliance, Vol: 2, ISSN: 2575-1077Salmonella enterica (e.g., serovars Typhi and Typhimurium) relies on translocation of effectors via type III secretion systems (T3SS). Specialization of typhoidal serovars is thought to be mediated via pseudogenesis. Here, we show that the Salmonella Typhi STY1076/t1865 protein, named StoD, a homologue of the enteropathogenic Escherichia coli/enterohemorrhagic E. coli/Citrobacter rodentium NleG, is a T3SS effector. The StoD C terminus (StoD-C) is a U-box E3 ubiquitin ligase, capable of autoubiquitination in the presence of multiple E2s. The crystal structure of the StoD N terminus (StoD-N) at 2.5 Å resolution revealed a ubiquitin-like fold. In HeLa cells expressing StoD, ubiquitin is redistributed into puncta that colocalize with StoD. Binding assays showed that StoD-N and StoD-C bind the same exposed surface of the β-sheet of ubiquitin, suggesting that StoD could simultaneously interact with two ubiquitin molecules. Consistently, StoD interacted with both K63- (KD = 5.6 ± 1 μM) and K48-linked diubiquitin (KD = 15 ± 4 μM). Accordingly, we report the first S. Typhi–specific T3SS effector. We suggest that StoD recognizes and ubiquitinates pre-ubiquitinated targets, thus subverting intracellular signaling by functioning as an E4 enzyme.
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Conference paperSelvarajah U, Blanco JM, Radhakrishnan S, et al., 2019,
IS AXIAL SPONDYLOARTHRITIS IN IBD DIFFERENT TO AXIAL SPONDYLOARTHRITIS WITHOUT IBD?
, Annual Meeting of the British-Society-of-Gastroenterology (BSG), Publisher: BMJ PUBLISHING GROUP, Pages: A96-A96, ISSN: 0017-5749 -
Conference paperSelvarajah U, Blanco JM, Radhakrishnan S, et al., 2019,
FAECAL CALPROTECTINSUGGESTS PRESENCE OF GUT INFLAMMATION IN AXIAL SPONDYLOARTHRITIS WITHOUT IBD
, Annual Meeting of the British-Society-of-Gastroenterology (BSG), Publisher: BMJ PUBLISHING GROUP, Pages: A95-A95, ISSN: 0017-5749 -
Journal articleEvans LE, Krishna A, Ma Y, et al., 2019,
Exploitation of antibiotic resistance as a novel drug target: development of a β-lactamase-activated antibacterial prodrug.
, Journal of Medicinal Chemistry, Vol: 62, Pages: 4411-4425, ISSN: 0022-2623Expression of β-lactamase is the single most prevalent determinant of antibiotic resistance, rendering bacteria resistant to β-lactam antibiotics. In this article, we describe the development of an antibiotic pro-drug that combines ciprofloxacin with a β-lactamase-cleavable motif. The pro-drug is only bactericidal after activation by β-lactamase. Bactericidal activity comparable to ciprofloxacin is demonstrated against clinically-relevant E. coli isolates expressing diverse β-lactamases; bactericidal activity was not observed in strains without β-lactamase. These findings demonstrate that it is possible to exploit antibiotic resistance to selectively target β-lactamase-producing bacteria using our pro-drug approach, without adversely affecting bacteria that do not produce β-lactamase. This paves the way for selective targeting of drug-resistant pathogens without disrupting or selecting for resistance within the microbiota, reducing the rate of secondary infections and subsequent antibiotic use.
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Journal articleSinganayagam A, Loo S-L, Calderazzo M, et al., 2019,
Anti-microbial immunity is impaired in COPD patients with frequent exacerbations
<jats:title>ABSTRACT</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Patients with frequent exacerbations represent a chronic obstructive pulmonary disease (COPD) sub-group requiring better treatment options. The aim of this study was to determine the innate immune mechanisms that underlie susceptibility to frequent exacerbations in COPD.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>We measured sputum expression of immune mediators and bacterial loads in samples from patients with COPD at stable state and during virus-associated exacerbations.<jats:italic>Ex vivo</jats:italic>immune responses to rhinovirus infection in differentiated bronchial epithelial cells (BECs) sampled from patients with COPD were additionally evaluated. Patients were stratified as frequent exacerbators (≥2 exacerbations in the preceding year) or infrequent exacerbators (<2 exacerbations in the preceding year) with comparisons made between these groups.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Frequent exacerbators had reduced sputum cell mRNA expression of the anti-viral immune mediators type I and III interferons and reduced interferon-stimulated gene (ISG) expression when clinically stable and during virus-associated exacerbation. RV-induction of interferon and ISGs<jats:italic>ex vivo</jats:italic>was also impaired in differentiated BECs from frequent exacerbators. Frequent exacerbators also had reduced sputum levels of the anti-microbial peptide mannose-binding lectin (MBL)-2 with an associated increase in sputum bacterial loads at 2 weeks following virus-associated exacerbation onset. MBL-2 levels correlated negatively with bacterial loads during exacerbation.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>These data imp
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